Intra-tumour diversification in colorectal cancer at the single-cell level

Sophie F. Roerink, Nobuo Sasaki, Henry Lee-Six, Matthew D. Young, Ludmil B. Alexandrov, Sam Behjati, Thomas J. Mitchell, Sebastian Grossmann, Howard Lightfoot, David A. Egan, Apollo Pronk, Niels Smakman, Joost Gorp, Elizabeth Anderson, Stephen J. Gamble, Chris Alder, Marc Wetering, Peter J. Campbell, Michael R. Stratton () and Hans Clevers ()
Additional contact information
Sophie F. Roerink: Wellcome Trust Sanger Insitute
Nobuo Sasaki: University Medical Center Utrecht and Princess Maxima Center
Henry Lee-Six: Wellcome Trust Sanger Insitute
Matthew D. Young: Wellcome Trust Sanger Insitute
Ludmil B. Alexandrov: University of California, San Diego
Sam Behjati: Wellcome Trust Sanger Insitute
Thomas J. Mitchell: Wellcome Trust Sanger Insitute
Sebastian Grossmann: Wellcome Trust Sanger Insitute
Howard Lightfoot: Wellcome Trust Sanger Insitute
David A. Egan: Center for Molecular Medicine, University Medical Centre Utrecht
Apollo Pronk: Diakonessenhuis
Niels Smakman: Diakonessenhuis
Joost Gorp: Diakonessenhuis
Elizabeth Anderson: Wellcome Trust Sanger Insitute
Stephen J. Gamble: Wellcome Trust Sanger Insitute
Chris Alder: Wellcome Trust Sanger Insitute
Marc Wetering: University Medical Center Utrecht and Princess Maxima Center
Peter J. Campbell: Wellcome Trust Sanger Insitute
Michael R. Stratton: Wellcome Trust Sanger Insitute
Hans Clevers: University Medical Center Utrecht and Princess Maxima Center

Nature, 2018, vol. 556, issue 7702, 457-462

Abstract: Abstract Every cancer originates from a single cell. During expansion of the neoplastic cell population, individual cells acquire genetic and phenotypic differences from each other. Here, to investigate the nature and extent of intra-tumour diversification, we characterized organoids derived from multiple single cells from three colorectal cancers as well as from adjacent normal intestinal crypts. Colorectal cancer cells showed extensive mutational diversification and carried several times more somatic mutations than normal colorectal cells. Most mutations were acquired during the final dominant clonal expansion of the cancer and resulted from mutational processes that are absent from normal colorectal cells. Intra-tumour diversification of DNA methylation and transcriptome states also occurred; these alterations were cell-autonomous, stable, and followed the phylogenetic tree of each cancer. There were marked differences in responses to anticancer drugs between even closely related cells of the same tumour. The results indicate that colorectal cancer cells experience substantial increases in somatic mutation rate compared to normal colorectal cells, and that genetic diversification of each cancer is accompanied by pervasive, stable and inherited differences in the biological states of individual cancer cells.

Date: 2018
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DOI: 10.1038/s41586-018-0024-3

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